A process for the preparation of a pyrrolidone intermediate

Abstract

The application provides a preparation method of a pyrrolidone intermediate. The method uses a continuous flow technology to obtain a target molecule through a substitution and a cyclization reaction of a cheap and readily available glutamic acid derivative and a halogenated ethylamine. The substitution reaction is directly used for the next step of the cyclization reaction without post-treatment. The total yield is greater than 80%, the chemical purity is greater than 99.1%, the optical purity is greater than 99.5% ee, the reaction safety factor is high, the cost is low, the efficiency is high, and the product yield and purity are high.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing a pharmaceutical intermediate, and more particularly to a method for synthesizing a pyrrolidone intermediate. Background Technology

[0002] Pfizer's oral drug Paxlovid has shown promising clinical efficacy against COVID-19.

[0003] Paxlovid consists of the SARS-CoV-2 3CL protease inhibitor Nirmatrelvir (PF-07321332) and the antiviral therapy ritonavir. Nirmatrelvir (PF-07321332) blocks the activity of the SARS-CoV-2 3CL protease, preventing subsequent viral RNA replication. Its structural formula is shown below:

[0004]

[0005] Retrosynthetic analysis of Nirmatrelvir (PF-07321332) suggests that the compound is obtained by amide condensation of the following three fragments.

[0006]

[0007] (2s,3s)-2-amino-3-[(2-pyrrolidone)]-propionitrile is an important fragment in the synthesis of Nirmatrelvir (PF-07321332), and (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolyl]propionate methyl ester is an important intermediate in the synthesis of this fragment.

[0008] Its molecular formula is as follows:

[0009]

[0010] The existing synthetic route for methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate is as follows:

[0011] 1. Using Boc-glutamic acid dimethyl ester as a raw material, it was first substituted with bromoacetonitrile, and then (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate methyl ester was synthesized through a series of reactions including reduction and cyclization (Reference 1: Tetrahedron Letters 42 (2001) 6807–6809; Reference 2: J. Med. Chem. 2020, 63, 4562-4578).

[0012]

[0013] 2. Starting from L-glutamic acid, Boc-glutamic acid dimethyl ester was first obtained, then it underwent a substitution reaction with bromoacetonitrile, and finally (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate methyl ester was synthesized through a series of reactions including reduction and cyclization. (Reference 3: Bioorg. Med. Chem. 13 (2005) 5240–5252; Reference 4: Sci. China. Chem. June (2012) Vol.55 No.6, 1101-1107)

[0014]

[0015] 3. Starting with L-glutamic acid, Boc-glutamic acid dimethyl ester was first obtained, then it underwent a substitution reaction with bromoacetonitrile, and finally (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolyl]propionate methyl ester was synthesized through a series of reactions including reduction and cyclization. (Reference 5: Journal of Medicinal Chemistry, 2006, Vol. 49, No. 16)

[0016]

[0017] 4. Using continuous flow technology, starting from amino-protected glutamate diester, a substitution reaction is first carried out with bromoacetonitrile, followed by a series of reactions including reduction and cyclization to synthesize methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolyl]propionate. (Reference 6: CN114230504A)

[0018]

[0019] The existing technology mainly uses glutamic acid derivatives to replace bromoacetonitrile and then perform reduction cyclization to prepare the intermediate (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidone]methyl propionate. The traditional method uses a reaction vessel, which has a long reaction time, complicated steps, and harsh reaction conditions. Therefore, how to obtain a new method for preparing pyrrolidone intermediates that is low-cost, environmentally friendly, and simple is a topic that needs to be further developed by those skilled in the art. Summary of the Invention

[0020] To address the shortcomings of existing technologies, this invention provides a method for synthesizing the pyrrolidone intermediate shown in Formula III, comprising the following steps:

[0021]

[0022] Wherein, R1 and R2 may be the same or different, and are independently selected from methyl or ethyl; Pg is an amino protecting group, such as Boc, Bn, Cbz; X is Cl, Br, or I;

[0023] (1) Compound I and compound I-1 were reacted under the action of base reagent 1 to obtain compound II;

[0024] (2) Compound II reacts with base reagent 2 to give compound III;

[0025] According to an embodiment of the present invention, in step (1), the reaction can be carried out in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, alkanes with fewer than C7 atoms (such as n-heptane, cyclohexane), acetone, toluene, and xylene;

[0026] According to an embodiment of the present invention, in step (1), the alkaline reagent 1 is selected from one or more of lithium methyl, lithium butyl, lithium n-hexyl, lithium sec-butyl, lithium phenyl, lithium tetramethylpiperidine, lithium diisopropylamino (LDA), lithium hexamethyldisilamide (LiHMDS), lithium amino, sodium hexamethyldisilamide (NaHMDS), sodium hydride, sodium metal, and potassium metal.

[0027] According to an embodiment of the present invention, in step (1), the molar ratio of compound I to base reagent 1 is 1:1 to 20, for example 1:1 to 10, and exemplary ratios are 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8.

[0028] According to an embodiment of the present invention, in step (1), the molar ratio of compound I to compound I-1 is 1:1 to 10, for example 1:1 to 3, such as 1:1, 1:1.1, 1:1.15, 1:1.2, 1:1.3, 1:2;

[0029] According to an embodiment of the present invention, in step (1), the reaction temperature is -20~20℃, for example -15~10℃.

[0030] According to an embodiment of the present invention, in step (2), the alkaline reagent 2 is selected from aprotic organic amines, such as one or more of triethylamine, diisopropylethylamine, and tetramethylguanidine;

[0031] According to an embodiment of the present invention, in step (2), the molar ratio of compound II to base reagent 2 is 1:1 to 10, for example 1:1 to 5, and exemplary examples are 1:1, 1:2, and 1:3;

[0032] According to an embodiment of the present invention, in step (2), the reaction temperature is 50~110℃, for example 90~100℃;

[0033] According to an embodiment of the present invention, in step (2), the reaction pressure is 0.1~2.0 MPa, for example 0.2~1.0 MPa, exemplarily 0.3 MPa, 0.4 MPa, or 0.5 MPa;

[0034] According to an embodiment of the present invention, step (2) further includes a post-processing step: the pH of the reaction solution after the reaction is completed is adjusted to 7-8 with 1-6 M hydrochloric acid, the solvent is removed under reduced pressure to obtain the crude product, and then the product is recrystallized with a methanol:acetone mixture to obtain the purified product.

[0035] According to an embodiment of the present invention, the weight ratio of methanol to acetone in the methanol:acetone mixture is 1:(3-8), for example, 1:4, 1:5, or 1:6.

[0036] According to an embodiment of the present invention, the synthesis method includes the following steps:

[0037]

[0038] Wherein, Pg is an amino protecting group, such as Boc, Bn, Cbz; X is Cl, Br, I;

[0039] (1) The solution of compound I' and the solution of alkaline reagent 1 are pumped into a continuous reactor, and then the solution of compound I-1 is pumped in to react and generate a reaction solution containing compound II'.

[0040] (2) The reaction solution containing compound II' is mixed with alkaline reagent 2 to obtain a mixed solution. After preheating, it is pumped into a fixed bed reaction device to obtain compound III'.

[0041] According to an embodiment of the present invention, in step (1), the solution of compound I', the solution of alkaline reagent 1 and the solution of compound I-1 can be tetrahydrofuran solutions of compound I', alkaline reagent 1 and compound I-1, respectively;

[0042] According to an embodiment of the present invention, in step (1), the flow rate of the solution of compound I' is 2~20 mL / min, for example 5~15 mL / min, exemplarily 6 mL / min, 8 mL / min, 10 mL / min, 12 mL / min;

[0043] According to an embodiment of the present invention, in step (1), the flow rate of the solution of the alkaline reagent 1 is 1.5~15 mL / min, for example 5~12 mL / min, and exemplary values ​​are 6 mL / min, 8.5 mL / min, 10.5 mL / min, and 11 mL / min;

[0044] According to an embodiment of the present invention, in step (1), the flow rate of the solution of compound I-1 is 2 to 10 mL / min, for example 3 to 8 mL / min, exemplarily 3 mL / min, 3.6 mL / min, 4 mL / min, and 5 mL / min;

[0045] According to an embodiment of the present invention, in step (1), the reaction temperature is -20~20℃, for example -15~10℃;

[0046] According to an embodiment of the present invention, in step (1), the residence time of the reaction liquid in the continuous reactor is 0.1 to 10 min, for example 0.5 to 5 min, and exemplary examples are 40 s, 1 min, and 2 min.

[0047] According to an embodiment of the present invention, in step (2), the flow rate of the mixed liquid is 3~20 mL / min, for example 5~10 mL / min, and exemplaryly 6 mL / min, 7 mL / min, and 8 mL / min;

[0048] According to an embodiment of the present invention, in step (2), the preheating temperature is 80~100℃, for example 90℃;

[0049] According to an embodiment of the present invention, in step (2), the residence time of the reaction liquid in the reaction device is 1 to 10 min, for example, 1 to 5 min, exemplarily 1 min, 2 min, 2.2 min, 3 min.

[0050] Beneficial effects

[0051] The method for preparing pyrrolidine intermediates provided by this invention employs continuous flow technology, allowing direct use of non-salt forms of haloethylamine without the need for in-situ free haloethylamine hydrochloride. It enables continuous sample injection, has a short reaction time, and avoids cyano reduction. This invention starts with inexpensive and readily available glutamic acid derivatives, undergoing a two-step substitution and cyclization reaction with haloethylamine to obtain the target molecule. After the substitution reaction, no post-processing is required, and the molecule can be directly used for the next cyclization reaction. The overall yield is greater than 80%, with a chemical purity of over 99.1% and an optical purity of over 99.5% ee. The method boasts high reaction safety, low cost, high efficiency, and high product yield and purity. Detailed Implementation

[0052] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0053] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0054] Example 1: Synthesis of dimethyl (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)glutarate

[0055] 275.2 g (1.0 mol) of N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester was dissolved in 1560 g of anhydrous tetrahydrofuran to obtain a 15% (w / w) feed solution. This feed solution was pre-cooled to -5°C using a temperature controller and used as the first reaction stream. A commercially available diisopropylaminolithium tetrahydrofuran solution (2 M, 2.5 L) was pre-cooled to 0°C and used as the second stream. Both streams were then simultaneously pumped into a microchannel reactor. The feed solution flow rate was 10 mL / min, the diisopropylaminolithium tetrahydrofuran solution flow rate was 10.5 mL / min, the proton extraction temperature was -15°C, and the proton extraction retention time was 50 seconds. A tetrahydrofuran solution (1.5 L) of bromoethylamine (142.6 g, 1.15 mol) was pre-cooled to 5 °C and used as the third stream. The alkylation reaction temperature of the protonated system of bromoethylamine solution and feed solution was 10 °C. The flow rate of bromoethylamine solution was 3.6 mL / min, and the retention time in the microchannel reactor was 40 seconds. The effluent was collected and cooled to obtain a dimethyl (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)glutarate solution. The product conversion rate could reach over 96%, which was directly used in the next step of the reaction.

[0056] Example 2 Synthesis of methyl S-2-((tert-Butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidine-3-yl)propionate

[0057] The above-mentioned (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)dimethyl glutarate solution and 202 g of triethylamine (2.0 eq) were mixed as the reaction feed for cyclization. The mixed liquid was preheated to 90°C in a preheater and then pumped into a microchannel reactor. The flow rate of the reaction feed was 6 mL / min, the reaction temperature was 100°C, the reaction pressure was 0.3 MPa, and the retention time in the fixed bed was 2.2 min. The effluent was collected and cooled to obtain the target product solution. The product conversion rate could reach over 98% (purity >94%). The combined elution system was adjusted to pH 7-8 using 3M hydrochloric acid, and tetrahydrofuran was removed under reduced pressure to obtain crude methyl S-2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopyrrolidine-3-yl)propionate. The crude product was then recrystallized from a methanol:acetone mixture (crude product to solvent weight ratio 1:8, methanol:acetone weight ratio 1:5). The product was filtered to obtain a white solid, which was dried under vacuum at 50°C (vacuum degree: -0.08 MPa) to obtain 238.3 g of white solid. The chemical purity was 99.4%, and the combined yield of the two continuous elution steps was 82.8%. The optical purity was 99.7% ee (chromatographic column: Chiralpak OD-H, detection wavelength: 210 nm, mobile phase: n-heptane:isopropanol = 9:1 plus 0.1% acetic acid, flow rate: 1 mL / min). 1 ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (br, 1H), 7.41 (d, J=8.0Hz, 1H), 4.06–4.00 (m, 1H), 3.63 (s, 3H), 3.32–3.12 (m, 2H), 2.52–2.50 (m, 1H), 2.34–2.28 (m, 1H), 2.17–1.95 (m, 1H), 1.71–1.53 (m, 2H), 1.35 (s, 9H). LC-MS calculated value: 286.15, measured value M+1: 287.1.

[0058] Example 3 Synthesis of dimethyl (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)glutarate

[0059] 275.3 g (1.0 mol) of N-tert-butoxycarbonyl-L-glutamic acid dimethyl ester was dissolved in 1560 g of anhydrous tetrahydrofuran to obtain a 15% (w / w) feed solution. The feed solution and hydrogen were preheated to -5°C using a preheater as the first reaction stream, and a commercially available hexamethyldisilamide lithium tetrahydrofuran solution (2M, 2.5 L) was preheated to 0°C as the second stream. Both streams were then simultaneously pumped into a microchannel reactor at a flow rate of 9 mL / min for the feed solution and 8.5 mL / min for the hexamethyldisilamide lithium tetrahydrofuran solution. The proton extraction temperature was -15°C, and the proton extraction retention time was 30 seconds. A tetrahydrofuran solution (1.5 L) of chloroethylamine (159.1 g, 2.0 mol) was pre-cooled to -5 °C and used as the third stream. The alkylation reaction temperature of the chloroethylamine solution and the feed solution in the deprotonation system was -10 °C. The flow rate of the chloroethylamine solution was 3.5 mL / min, and the retention time in the microchannel reactor was 80 seconds. The effluent was collected and cooled to obtain a dimethyl (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)glutarate solution. The product conversion rate could reach over 96%, which was directly used in the next step of the reaction.

[0060] Example 4 Synthesis of methyl S-2-((tert-Butoxycarbonyl)amino)-3((S)-2-oxopyrrolidine-3-yl)propionate

[0061] The above-mentioned (2S,4S)-2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)dimethyl glutarate solution and 252.5 g of triethylamine (2.5 eq) were mixed as the cyclization reaction feed. The mixed liquid was preheated to 95°C in a preheater and then pumped into a microchannel reactor. The flow rate of the reaction feed was 12 mL / min, the reaction temperature was 110°C, the reaction pressure was 0.4 MPa, and the retention time in the fixed bed was 2 min. The effluent was collected and cooled to obtain the target product solution. The product conversion rate could reach over 98% (purity >94%). The combined elution system was adjusted to pH 7-8 with 2M hydrochloric acid, and tetrahydrofuran was removed under reduced pressure to obtain crude methyl S-2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopyrrolidine-3-yl)propionate. The crude product was then recrystallized from a methanol:acetone mixture (weight ratio 1:5), filtered to obtain a white solid, and dried under vacuum at 50°C (vacuum degree: -0.08 MPa) to obtain 214.5 g of white solid. The chemical purity was 99.1%, and the combined yield of the two continuous elution steps was 80.3%. The optical purity was 99.5% ee (chromatographic column: Chiralpak OD-H, detection wavelength: 210 nm, mobile phase: n-heptane:isopropanol = 9:1 plus 0.1% acetic acid, flow rate: 1 mL / min). 1¹H NMR (400 MHz, CDCl₃) δ: 7.64 (br, 1H), 7.41 (d, J=8.0Hz, 1H), 4.06–4.00 (m, 1H), 3.63 (s, 3H), 3.32–3.12 (m, 2H), 2.52–2.50 (m, 1H), 2.34–2.28 (m, 1H), 2.17–1.95 (m, 1H), 1.71–1.53 (m, 2H), 1.35 (s, 9H). LC-MS calculated value: 286.15, measured value M+1: 287.1.

[0062] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of this application.

Claims

1. A method for synthesizing a pyrrolidone intermediate of Formula III', comprising the following steps: Wherein, Pg is an amino protecting group; X is Cl, Br, or I; (1) The solution of compound I' and the solution of alkaline reagent 1 are pumped into a microchannel reactor, and then the solution of compound I-1 is pumped in to generate a reaction solution containing compound II'. (2) The reaction solution containing compound II' is mixed with alkaline reagent 2 to obtain a mixed solution, which is preheated and then pumped into a microchannel reactor to obtain compound III'; Alkali reagent 1 is selected from one or more of lithium methyl, lithium butyl, lithium n-hexyl, lithium phenyl, lithium tetramethylpiperidine, lithium diisopropylamino, lithium hexamethyldisilamide, lithium amino, and sodium hexamethyldisilamide. In step (2), the alkaline reagent 2 is selected from aproton-free organic amines, and the aproton-free organic amines are selected from one or more of triethylamine, diisopropylethylamine, and tetramethylguanidine.

2. The method according to claim 1, characterized in that, In step (1), the reaction is carried out in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, cyclohexane, acetone, toluene, and xylene.

3. The method according to claim 1, characterized in that, In step (1), Pg is selected from Boc, Bn, and Cbz.

4. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound I' to base reagent 1 is 1:1~20.

5. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound I' to compound I-1 is 1:1~10.

6. The method according to claim 1, characterized in that, In step (1), the reaction temperature is -20~20℃.

7. The method according to claim 1, characterized in that, In step (2), the molar ratio of compound II' to base reagent 2 is 1:1~10.

8. The method according to claim 1, characterized in that, The reaction temperature in step (2) is 50~110℃; The reaction pressure in step (2) is 0.1~2.0 MPa.

9. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound I' to base reagent 1 is 1:1~10.

10. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound I' to compound I-1 is 1:1~3.

11. The method according to claim 1, characterized in that, In step (1), the reaction temperature is -15~10℃.

12. The method according to claim 1, characterized in that, In step (2), the molar ratio of compound II' to base reagent 2 is 1:1~5.

13. The method according to claim 1, characterized in that, The reaction temperature in step (2) is 90~100℃; The reaction pressure in step (2) is 0.2~1.0 MPa.

14. The method according to claim 1, characterized in that, Step (2) also includes a post-processing step: after the reaction is completed, the pH of the reaction solution is adjusted to 7-8 with 1-6 M hydrochloric acid, the solvent is removed under reduced pressure to obtain the crude product, and then the product is recrystallized from the methanol:acetone mixture to obtain the purified product. The methanol:acetone mixture has a methanol:acetone weight ratio of 1:(3-8).

15. The method according to claim 1, characterized in that, In step (1), the solution of compound I', the solution of alkali reagent 1, and the solution of compound I-1 are tetrahydrofuran solutions of compound I', alkali reagent 1, and compound I-1, respectively.

16. The method according to claim 1, characterized in that, In step (1), the flow rate of the solution of compound I' is 2~20 mL / min.

17. The method according to claim 1, characterized in that, In step (1), the flow rate of the alkaline reagent 1 solution is 1.5~15 mL / min.

18. The method according to claim 1, characterized in that, In step (1), the flow rate of the solution of compound I-1 is 2~10 mL / min.

19. The method according to claim 1, characterized in that, In step (1), the residence time of the reaction solution in the microchannel reactor is 0.1~10 min.

20. The method according to claim 1, characterized in that, In step (2), the flow rate of the mixed liquid is 3~20mL / min.

21. The method according to claim 1, characterized in that, In step (2), the preheating temperature is 80~100℃.

22. The method according to claim 1, characterized in that, In step (2), the residence time of the reaction solution in the microchannel reactor is 1~10 min.

23. The method according to claim 1, characterized in that, In step (1), the flow rate of the solution of compound I' is 5~15 mL / min.

24. The method according to claim 1, characterized in that, In step (1), the flow rate of the alkaline reagent 1 solution is 5~12 mL / min.

25. The method according to claim 1, characterized in that, In step (1), the flow rate of the solution of compound I-1 is 3~8 mL / min.

26. The method according to claim 1, characterized in that, In step (1), the residence time of the reaction solution in the microchannel reactor is 0.5~5 min.

27. The method according to claim 1, characterized in that, In step (2), the flow rate of the mixed liquid is 5~10 mL / min.

28. The method according to claim 1, characterized in that, In step (2), the residence time of the reaction solution in the microchannel reactor is 1 to 5 minutes.

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